Recent studies have demonstrated that microRNA (miRNA) signaling pathways play a prominent role in regulating behavioral responses to cocaine. Therefore, studies aimed at understanding how the miRNA system operates are directly relevant to drug abuse research. Recent studies also indicate that the translin/trax RNAse complex plays a key role in miRNA processing. Furthermore, we have found, in preliminary studies, that translin knockout mice display reduced locomotor responses to cocaine. Accordingly, we plan to define: 1) the role of the translin/trax complex in regulating miRNA processing, and 2) its role in regulating responsiveness to cocaine. Accordingly, the specific aims of the proposed project are to: I. Identify direct miRNA targets of the translin/trax RNAse complex and determine its role in their processing. Although the translin/trax complex has been implicated in processing miRNAs, it is still unclear which specific miRNAs it targets directly. Accordingly, we plan to use a highly efficient UV-crosslinking procedure (PAR- CLIP) to identify RNAs that bind directly to the translin/trax complex in intact cells. II. Determine the impact of translin deletion on signaling pathways that regulate responsiveness to cocaine. As translin and trax are expressed in striatal neurons, a major site of cocaine action, we plan, in this set of studies, to conduct both candidate-based and screening approaches to identify alterations in striatal signaling pathways caused by translin deletion. III. Determine whether deletion of translin from striatal neurons mediates altered responsiveness to cocaine. Our initial studies demonstrating that translin deletion impairs the locomotor response to cocaine were performed in conventional ko mice. Accordingly, we plan, in this set of studies, to generate and use translin conditional ko mice to test the hypothesis that deletion of translin from D1R- and/or D2R-positive neurons mediates this behavioral phenotype.